7q6s - Revision history

OCA at 13:14, 1 February 2024

OCA — Thu, 01 Feb 2024 13:14:41 GMT

←Older revision		Revision as of 13:14, 1 February 2024
Line 1:		Line 1:

	==Keap1 compound complex==		==Keap1 compound complex==
-	<StructureSection load='7q6s' size='340' side='right'caption='[[7q6s]]' scene=''>	+	<StructureSection load='7q6s' size='340' side='right'caption='[[7q6s]], [[Resolution\|resolution]] 2.14Å' scene=''>
	== Structural highlights ==		== Structural highlights ==
-	<table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7Q6S OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7Q6S FirstGlance]. <br>	+	<table><tr><td colspan='2'>[[7q6s]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7Q6S OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7Q6S FirstGlance]. <br>
-	</td></tr><tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=7q6s FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7q6s OCA], [https://pdbe.org/7q6s PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7q6s RCSB], [https://www.ebi.ac.uk/pdbsum/7q6s PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7q6s ProSAT]</span></td></tr>	+	</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models\|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution\|Resolution]] 2.143Å</td></tr>
		+	<tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=91M:(5S,8R)-16-(2,1,3-benzoxadiazol-4-yl)-8-[[(2S)-1-ethanoylpyrrolidin-2-yl]carbonylamino]-N,N-dimethyl-7,11-bis(oxidanylidene)-10-oxa-3-thia-6-azabicyclo[10.4.0]hexadeca-1(16),12,14-triene-5-carboxamide'>91M</scene>, <scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene></td></tr>
		+	<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=7q6s FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7q6s OCA], [https://pdbe.org/7q6s PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7q6s RCSB], [https://www.ebi.ac.uk/pdbsum/7q6s PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7q6s ProSAT]</span></td></tr>
	</table>		</table>
		+	== Function ==
		+	[https://www.uniprot.org/uniprot/KEAP1_HUMAN KEAP1_HUMAN]
		+	<div style="background-color:#fffaf0;">
		+	== Publication Abstract from PubMed ==
		+	Upregulation of the transcription factor Nrf2 by inhibition of the interaction with its negative regulator Keap1 constitutes an opportunity for the treatment of disease caused by oxidative stress. We report a structurally unique series of nanomolar Keap1 inhibitors obtained from a natural product-derived macrocyclic lead. Initial exploration of the structure-activity relationship of the lead, followed by structure-guided optimization, resulted in a 100-fold improvement in inhibitory potency. The macrocyclic core of the nanomolar inhibitors positions three pharmacophore units for productive interactions with key residues of Keap1, including R415, R483, and Y572. Ligand optimization resulted in the displacement of a coordinated water molecule from the Keap1 binding site and a significantly altered thermodynamic profile. In addition, minor reorganizations of R415 and R483 were accompanied by major differences in affinity between ligands. This study therefore indicates the importance of accounting both for the hydration and flexibility of the Keap1 binding site when designing high-affinity ligands.
		+
		+	Importance of Binding Site Hydration and Flexibility Revealed When Optimizing a Macrocyclic Inhibitor of the Keap1-Nrf2 Protein-Protein Interaction.,Begnini F, Geschwindner S, Johansson P, Wissler L, Lewis RJ, Danelius E, Luttens A, Matricon P, Carlsson J, Lenders S, Konig B, Friedel A, Sjo P, Schiesser S, Kihlberg J J Med Chem. 2022 Feb 24;65(4):3473-3517. doi: 10.1021/acs.jmedchem.1c01975. Epub , 2022 Feb 2. PMID:35108001<ref>PMID:35108001</ref>
		+
		+	From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
		+	</div>
		+	<div class="pdbe-citations 7q6s" style="background-color:#fffaf0;"></div>
		+	== References ==
		+	<references/>
	__TOC__		__TOC__
	</StructureSection>		</StructureSection>
		+	[[Category: Homo sapiens]]
	[[Category: Large Structures]]		[[Category: Large Structures]]
	[[Category: Johansson P]]		[[Category: Johansson P]]

OCA at 06:15, 16 March 2022

OCA — Wed, 16 Mar 2022 06:15:35 GMT

←Older revision		Revision as of 06:15, 16 March 2022
Line 1:		Line 1:
-	'''Unreleased structure'''

-	~~The entry~~ 7q6s ~~is ON HOLD until Paper Publication~~	+	==Keap1 compound complex==
-		+	<StructureSection load='7q6s' size='340' side='right'caption='[[7q6s]]' scene=''>
-	~~Authors~~: ~~Johansson~~, P.	+	== Structural highlights ==
-		+	<table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7Q6S OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7Q6S FirstGlance]. <br>
-	~~Description: Keap1 compound complex~~	+	</td></tr><tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=7q6s FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7q6s OCA], [https://pdbe.org/7q6s PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7q6s RCSB], [https://www.ebi.ac.uk/pdbsum/7q6s PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7q6s ProSAT]</span></td></tr>
-	[[Category: ~~Unreleased~~ Structures]]	+	</table>
-	[[Category: Johansson, P]]	+	__TOC__
		+	</StructureSection>
		+	[[Category: Large Structures]]
		+	[[Category: Johansson P]]

OCA at 15:31, 15 December 2021

OCA — Wed, 15 Dec 2021 15:31:04 GMT

←Older revision		Revision as of 15:31, 15 December 2021
Line 1:		Line 1:
	'''Unreleased structure'''		'''Unreleased structure'''

-	The entry 7q6s is ON HOLD	+	The entry 7q6s is ON HOLD until Paper Publication

	Authors: Johansson, P.		Authors: Johansson, P.

OCA: Protected "7q6s" [edit=sysop:move=sysop]

OCA — Wed, 17 Nov 2021 12:04:31 GMT

Protected "7q6s" [edit=sysop:move=sysop]

←Older revision

Revision as of 12:04, 17 November 2021

OCA: New page: '''Unreleased structure''' The entry 7q6s is ON HOLD Authors: Johansson, P. Description: Keap1 compound complex Category: Unreleased Structures Category: Johansson, P

OCA — Wed, 17 Nov 2021 12:04:30 GMT

New page: '''Unreleased structure''' The entry 7q6s is ON HOLD Authors: Johansson, P. Description: Keap1 compound complex Category: Unreleased Structures Category: Johansson, P

New page

'''Unreleased structure'''

The entry 7q6s is ON HOLD

Authors: Johansson, P.

Description: Keap1 compound complex
[[Category: Unreleased Structures]]
[[Category: Johansson, P]]